Project Summary Aging is associated with increased adiposity, that induces low grade chronic inflammation in many tissues, termed ?inflamm-aging?. This metabolically-triggered inflammation, aka meta-inflammation, underlies pathological processes of many age-associated diseases and is a hallmark of aging. Macrophages are a major immune-mediator of meta-inflammation. Macrophages consist of pro-inflammatory M1 and anti-inflammatory M2 cells, which undergo dynamically polarization to either M1 and M2 state in response to environmental cues. Macrophage polarization is impaired in aging, which contributes to inflamm-aging. Macrophage anti- inflammatory reprogramming has potential to prevent/reverse meta-inflammation in aging. However, the regulatory mechanisms of macrophage polarization are not well understood. Growth hormone secretagogue receptor (GHS-R), is a known receptor for nutrient-sensing gut hormone ghrelin. We have found that global GHS- R ablation protects against obesity, insulin resistance, adipose tissue inflammation and nonalcoholic steatohepatitis (NASH) in aging. GHS-R is highly expressed in macrophages and its expression increases in aging. In contrast, GHS-R expression is undetectable in hepatocytes and very low in adipocytes. Our gene knockdown study indicates that GHS-R has cell-autonomous effects in macrophages. Our preliminary data have suggested that GHS-R deletion down-regulates key insulin signaling mediators insulin receptor substrate-2 (IRS2) and protein kinase Akt in macrophages. Hence, we hypothesize that GHS-R is a key regulator of macrophage polarization in aging. Specifically, GHS-R activates the IRS2-Akt pathway to metabolically reprogram macrophages to promote pro-inflammatory polarization during aging, leading to meta- inflammation in adipose tissues and liver. To unravel the roles and pertinent mechanisms of GHS-R in macrophage reprogramming and meta-inflammation, we have generated myeloid-specific GHS-R knockout and re-expressing mice. The following comprehensive and complementary Specific Aims will be tested: 1. Determine the role of GHS-R in macrophage polarization, and its effect on adipose and hepatic meta-inflammation during aging (in vivo studies); 2. Interrogate the cellular mechanisms by assessing cell-autonomous effect of GHS-R in macrophages, and paracrine effect of GHS-R deficient/re-expressing macrophages on adipocytes and hepatocytes (ex vivo studies); 3. Delineate molecular mechanisms by which GHS-R regulates macrophage polarization. We anticipate that during aging, GHS-R activates insulin signaling pathway to upregulate anabolic glycolysis and down-regulate fatty acid oxidation pathways, thus promoting pro-inflammatory polarization. This proposal will shed light on a new paradigm for metabolic reprogramming of macrophages during aging, and will likely uncover a novel regulatory mechanism linking nutrient sensing signaling and metabolic regulatory pathways in macrophages. This proposal will also provide ?proof-of-concept? evidence for whether targeting GHS-R in macrophages would be a unique and powerful strategy for combating inflamm-aging.